Papillomaviruses induce persistent epithelial lesions, known as papillomas. Genital papillomavirus infection is widespread and associated with the development of cervical cancer. The viral E2 proteins regulate viral transcription, replication and episomal genome maintenance. Our aim is to elucidate the mechanisms by which the E2 proteins control the viral life cycle. We have shown that papillomavirus genomes and the E2 transactivator protein interact with cellular mitotic chromosomes in dividing cells. This ensures that viral genomes are properly segregated to daughter cells and are retained within the nucleus. The E2 transactivation domain of E2 interacts with the host chromosomes and we have identified potential interaction surfaces of this domain. We have also identified distinct regions of E2 important for replication, E1 interaction and transcriptional repression and shown that chromosome binding correlates with the recently identified cellular chromosomal tethering protein, Brd4. We have shown that E2 cannot segregate plasmids with E2-binding sites in Sacchromyces cerevisiae but that segregation can be rescued by expression of the Brd4 gene. We have expressed a series of E2 proteins from many different human and animal papillomaviruses and have shown that most of them have the ability to associate with cellular mitotic chromosomes. We have shown that phosphorylation by CK2 induces a conformational change in the E2 protein that leads to ubiquination and proteasomal degradation. E2 protein half-life in turn determines viral genome copy number. In most cervical cancers, papillomavirus DNA is found integrated into cellular chromosomes instead of replicating episomally. This integration disrupts the E1 and/or E2 genes and this has led to the hypothesis that disruption of these regulatory functions is a critical step in malignant progression. To study the mechanism of this progression we have developed a system to immortalize primary human keratinocyte cells containing hybrid papillomavirus genomes that are maintained episomally in the absence of E1 and E2 gene functions. We have used this system to determine the E2 regulatory functions responsible for HPV oncogene expression and we have shown that this regulation can change at different times after infection, based on the chromatin structure of the viral genomes.